Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX, United States.
Stony Brook University Pain and Analgesia Research Center (SPARC) and Department of Anesthesiology, Stony Brook University, Stony Brook, NY, United States.
Pain. 2023 Feb 1;164(2):402-412. doi: 10.1097/j.pain.0000000000002715. Epub 2022 Jun 16.
Nociplastic pain conditions develop predominantly in women. We recently established a murine nociplastic pain model by applying postinjury thermal (40°C) stimulation to an injured (capsaicin-injected) area, triggering a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. The nociplastic pain state was centrally maintained by spinal microglia in males but peripherally by ongoing afferent activity at the previously injured area in females. Here, we investigated whether gonadal hormones are critical for the development of this peripherally maintained nociplastic pain state in females. Although the transition to a nociplastic pain state still occurred in ovariectomized females, the pain state was maintained neither by ongoing afferent activity at the previously injured area nor by spinal microglia. Estradiol reconstitution a week before the injury plus postinjury stimulation, but not after the transition had already occurred, restored the development of peripherally maintained nociplastic mechanical hypersensitivity in ovariectomized females. G protein-coupled estrogen receptor antagonism during the transition phase mimicked ovariectomy in gonad-intact females, whereas the receptor antagonism after the transition gradually alleviated the nociplastic mechanical hypersensitivity. At the previously injured area, afferents responsive to allyl isothiocyanate (AITC), a TRPA1 agonist, contributed to the maintenance of nociplastic mechanical hypersensitivity in gonad-intact females. In ex vivo skin-nerve preparations, only AITC-responsive afferents from the nociplastic pain model in gonad-intact females showed ongoing activities greater than control. These results suggest that gonadal hormones are critical for peripherally maintained nociplastic pain state in females by sensitizing AITC-responsive afferents to be persistently active.
伤害感受性疼痛主要发生在女性中。我们最近通过对受伤（辣椒素注射）区域施加受伤后热（40°C）刺激，建立了一种啮齿动物伤害感受性疼痛模型，从而引发了一种向伤害感受性疼痛状态的转变，表现为在先前受伤区域之外持续出现机械性超敏反应。在雄性中，伤害感受性疼痛状态由脊髓小胶质细胞维持，而在雌性中则由先前受伤区域的持续传入活动维持。在这里，我们研究了性腺激素是否对女性中这种由外周维持的伤害感受性疼痛状态的发展至关重要。尽管去卵巢的雌性仍然会向伤害感受性疼痛状态转变，但先前受伤区域的传入活动和脊髓小胶质细胞都不能维持疼痛状态。在受伤前一周加受伤后刺激时补充雌二醇，但在转变已经发生后则不行，这恢复了去卵巢雌性中由外周维持的伤害感受性机械性超敏反应的发展。在转变阶段进行 G 蛋白偶联雌激素受体拮抗作用类似于对完整性腺雌性进行卵巢切除术，而在转变后进行受体拮抗作用则逐渐缓解伤害感受性机械性超敏反应。在先前受伤区域，对丙烯基异硫氰酸酯（AITC）有反应的传入神经，一种 TRPA1 激动剂，有助于维持完整性腺雌性的伤害感受性机械性超敏反应。在离体皮肤-神经标本中，只有完整性腺雌性的伤害感受性疼痛模型中对 AITC 有反应的传入神经表现出大于对照的持续活动。这些结果表明，性腺激素通过使 AITC 反应传入神经持续活跃，对女性由外周维持的伤害感受性疼痛状态至关重要。
